POS0336 PERIPHERAL IMMUNOME DYSREGULATIONS REFLECT OSTEOARTHRITIS (OA) JOINT DISEASE SEVERITY
Authors: A. Chia, A. M. Lajam, G. Ang, M. Wasser, P. Kumar, K. Leung, S. Albani
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Osteoarthritis (OA) is a prevalent condition that is especially common among people of advanced ages. It is due to cartilage degeneration which leads to loss of mobility and chronic pain. Currently, there is no disease-modifying drugs to treat OA and the standard of care is pain management, and eventual joint replacement for end-stage disease. It is recognized that OA pathogenesis involves a complex interplay of joint damage, poor cartilage regeneration, and inflammation. However, much is unknown how the peripheral immunome architecture is perturbed by the local joint inflammation. <h3>Objectives</h3> To investigate how the peripheral immunome is dysregulated by local joint inflammation as a result of knee OA, and whether different immune subsets are dysregulated at different stages of OA severity. <h3>Methods</h3> We employed the use of mass cytometry time-of-flight (CyTOF) to investigate peripheral blood mononuclear cells (PBMCs) obtained from patients with OA and healthy controls (HCs). 64 patients with different severity of OA, based on radiographic Kellgren-Lawrence scores, and 37 age, sex, and race-matched HCs were enrolled in this study. To broadly capture the dysregulations in the different immune subsets, we designed two CyTOF marker panels that cover major innate and adaptive immune cell lineages to interrogate these samples. To investigate possible relationships between the peripheral and joint immunome dysregulations, digital deconvolution of RNA-sequencing data obtained from OA synovial samples to estimate immune subset frequency changes in the joint was also conducted. <h3>Results</h3> We observed dysregulations in both the innate and adaptive compartments of the OA peripheral immunome as compared to HCs, and different immune subsets were dysregulated at different OA severity. In early OA, there is an involvement of inflammatory immune subsets, namely natural killer (NK) and gamma-delta T cells, suggesting the possibility of these subsets infiltrating the joint to initiate and perpetuate joint inflammation in OA. As the disease progresses to late OA, we discovered further involvement of CD45RO+ and CTLA-4+/PD-1+ T cell subsets suggesting memory formation and immune exhaustion. Furthermore, we also observed an involvement of regulatory subsets in late OA suggesting the homeostatic attempts to temper the chronic inflammation at the OA joint. Comparing with our analysis of the digital deconvolution of RNA-seq data of OA synovia, NK cells, monocytes, gamma-delta T cells, and resting memory T cell subsets were found to be dysregulated in both the peripheral and joint immunomes, suggesting possible trafficking dynamics and functional relationship between the two immunomes. <h3>Conclusion</h3> Our study revealed dynamic peripheral immunome changes that provide insights to the immunopathogenesis of OA. By uncovering these underlying peripheral immunome disruptions in OA, we provide further evidence that the immune system plays an important role in OA disease process. <h3>Acknowledgements</h3> This research was supported by Duke-NUS Medical School under the Duke/Duke-NUS Research Collaboration Award (Duke/Duke-NUS/RECA/2012/2005), National Research Foundation Singapore under its National Medical Research Countil (NMRC)'s Transition Award Grant (CIRB Ref. No.:2019/2094) and NMRC Clinician-Scientist Award: Investigator Category (NMRC/CSA-INV/0022/2017), and Ministry of Health, Singapore, under its MOH Health Services Research Competitive Research Grant (HSR-CRG) (HSRG14may017). <h3>Disclosure of Interests</h3> Alfred Chia: None declared, Ahmad Mohamed Lajam: None declared, Gladys Ang: None declared, Martin Wasser: None declared, pavanish Kumar: None declared, Katy Leung Speakers bureau: AbbVie, DKSH, Janssen, Novartis, and Pfizer, Salvatore Albani: None declared.